The mechanism by which tumours are induced in experimental animals after administration of simple N-nitroso- carcinogens, such as dimethylnitrosamine and N-methyl-N-nitrosourea, will be investigated. They are readily synthesized in a radioactively labelled form and the products of their reaction with cellular components in tissues have been characterized. Certain organs are much more susceptible to the carcinogenic stimulus than others and this susceptibility varies with the physiological state of the animal and the dose of carginogen employed. The hypothesis that the initial carcinogenic stimulus produced by these agents results from the alkylation of DNA at the O6- position of guanine (and possibly other positions) and that the difference in susceptibility between different tissues is due to a difference in the ability to remove the alkylated product from DNA before cell division will be studied. The enzymatic mechanism resulting in the removal of O6-alkylguanine from DNA in various mammalian cells will be studied and a suitable assay procedure for the determination of this activity developed. The reasons for the large difference in the rate of loss of this product from kidney DNA after a low dose of dimethylnitrosamine (which does not induce the kidney tumours) and a high dose (which does produce renal tumours) will be investigated and related to the greater susceptibility of the kidney than the liver to carcinogenesis by the large dose. Although the production of human cancer by nitroso- compounds has not been demonstrated unequivocally, it is likely that man is susceptible to these compounds which are carcinogenic in many other species. Man is exposed to low levels of nitrosamines and nitrosamides due to their presence in certain foods and their formation from secondary amines and nitrate at acid pH in the stomach. The possible existence of a repair system capable of removing the products of interaction with DNA responsible for tumour induction, therefore, has an important bearing on the question of whether there is a 'safe low-level' of exposure to these agents below which no tumours would be expected. The knowledge of the physiological factors affecting this process might enable groups at high risk to be identified.